Mechanistic underpinnings of increased adipose tissue in HFpEF

心力衰竭（HF）是每年> 100万次住院治疗的主要诊断，其中“HF伴 射血分数保留（HFpEF），占所有临床HF表现的50%。但尽管 这一点及其对不断上升的医疗保健成本的影响，目前还没有针对HFpEF的循证疗法。这 部分原因是对HFpEF的发病机制缺乏了解， HFpEF需要量身定制的个性化方法。大型结局试验和登记研究表明，HFpEF是 异质表型和超重/肥胖是主要的风险因素（70-84%）。同样，约45%的 HFpEF患者肥胖，尽管肥胖本身与HF的未来发展有关， 调整已确定的风险因素。肥胖症中的肥胖增加会促进炎症和高血压 这可能有助于HFpEF的病理生理学。 棕色脂肪组织（BAT）在调节全身能量平衡中起着关键作用。无论是 啮齿动物和人类，有两种类型的产热脂肪细胞：经典的棕色脂肪细胞和 米色/“brite”脂肪细胞。后者是BAT，出现在白色脂肪组织中以响应刺激 经过一个称为“布朗宁”的过程。“布朗宁”最近被证明发生在精瘦的，代谢健康的 HFpEF小鼠，但这些发现的相关性和翻译意义是未知的，因为布朗宁 可能在应激源如癌症相关的恶病质或大面积烧伤时被激活。因此 布朗宁是有害的还是一种适应性应激反应，以及它是否可以作为一种 肥胖相关疾病的治疗靶点，如HFpEF。本翻译的主要目的 因此，建议剖析HFpEF中白色脂肪组织中布朗宁的调节，并探索 这些发现的临床意义。我们将探讨两个具体目标： 目的1：探讨肥胖HFpEF患者脂肪组织布朗宁与HFpEF的关系 以及这些与急性临床失代偿和HFpEF的关系 进展 在一项针对肥胖HFpEF患者的纵向、前瞻性研究中，急性HFpEF失代偿（定义为 （i）皮下白色脂肪组织中增加的布朗宁，（ii） 增加促血管生成因子（VEGF-A和ANG-1）的循环水平，降低抗血管生成因子（VEGF-A和ANG-1）的循环水平。 因子（ANGPTL-4和ANG-2）和（iii）急性HF入院期间血管生成因子的变化， 与定义为LV舒张功能障碍恶化、急性临床失代偿的临床结局相关 并预测再入院时间。 目的2：探讨HFpEF在脂肪组织布朗宁和血管生成中的作用，以及HFpEF对脂肪组织褐变和血管生成的影响。 增加的布朗宁激活对HFpEF的进展，在肥胖的HFRF 1大鼠。

Heart failure (HF) is the major diagnosis in >1 million hospitalizations annually, with “HF with preserved ejection fraction” (HFpEF), accounting for up to 50% of all clinical HF presentations. Yet, despite this and its impact on escalating health care costs, there are no evidence-based therapies for HFpEF. This stems, in part, from a lack of mechanistic understanding about the pathogenesis of HFpEF and that a more tailored, personalized approach is needed for HFpEF. Large outcome trials and registries reveal that HFpEF is a heterogeneous phenotype and being overweight/obese is a major risk factor (70-84%). Likewise, ~45% of patients with HFpEF are obese and obesity, in itself, is associated with the future development of HF despite adjusting for established risk factors. Increased adiposity in obesity promotes inflammation and hypertension which may contribute to HFpEF pathophysiology. Brown adipose tissue (BAT) plays a pivotal role in regulating whole-body energy balance. In both rodents and humans, there are two types of thermogenic adipocytes: classical brown adipocytes and beige/“brite” adipocytes. The latter are BAT that appears among white adipose tissue in response to a stimulus through a process termed “browning”. “Browning” was recently shown to occur in lean, metabolically healthy HFpEF mice but the relevance and translational implications of these findings are unknown since browning may be activated in response to stressors, such as cancer-associated cachexia or massive burns. Therefore it is unknown whether browning is deleterious or an adaptive stress response and whether it may serve as a therapeutic target for obesity-associated diseases, such as HFpEF. The broad objective of this translational proposal is therefore to dissect the regulation of browning in white adipose tissue in HFpEF and to explore the clinical relevance of these findings. We will explore 2 specific aims: Aim 1: To investigate in patients with obese HFpEF, the relationship between adipose tissue browning and angiogenesis and how these correlate with acute clinical decompensation and HFpEF progression. In a longitudinal, prospective study in obese patients with HFpEF, acute HFpEF decompensation (defined as a hospital admission) is associated with: (i) increased browning in subcutaneous white adipose tissue, (ii) increased circulating levels of pro-angiogenic factors (VEGF-A and ANG-1) and decreased anti-angiogenic factors (ANGPTL-4 and ANG-2) and (iii) changes in angiogenic factors during the acute HF admission, associates with clinical outcomes defined as worsened LV diastolic dysfunction, acute clinical decompensation and predicts time-to-readmission. Aim 2: To investigate the role of HFpEF in browning and angiogenesis in adipose tissue and the effect of increased browning activation on HFpEF progression in obese ZSF1 rats.